Comparing Preliminary Telehealth Outcomes to In-Person Delivery of a Rehabilitation Program for Stroke Survivors with Aphasia

Background. Aphasia is a language impairment, typically resulting from left hemisphere strokes. Aphasia impairs the neural networks that allow individuals to read, write/type, speak, and understand spoken information, negatively impacting daily communication and quality of life. Intensive Comprehensive Aphasia Programs (ICAPs) are stroke rehabilitation programs that help people living with aphasia improve their language function, communicative participation, and quality of life. In response to COVID-19, ICAPs could no longer take place in-person, necessitating a rapid move to telehealth models. No evidence has been provided in the literature to demonstrate the efficacy or effectiveness of telehealth ICAPs. Purpose. The purpose of this project was to compare language outcomes across two methods of ICAP delivery: telehealth (summer 2020) and in-person (summers 2014-2019). Methods. Participants. Stroke survivors with chronic aphasia participated in in-person or telehealth ICAPs at the University of Montana (UMT). Five stroke survivors participated in the novel summer 2020 UMT telehealth ICAP (IRB #87-20). Fifty-three stroke survivors participated in 2014-2019 UMT in-person ICAPs (IRB #116-14). Procedures. Language outcomes were evaluated using the Western Aphasia Battery-Revised (WAB-R) aphasia quotient (AQ). Individual characteristics of the telehealth participants were matched with participants from the 2014-2019 in-person data set. Three participant characteristics were considered during this matching process: (1) age (+/- 10 years), (2) biological sex, and (3) time post-stroke (+/- 6 months). Pre- and post-ICAP WAB-R AQ scores were compared across telehealth and in-person participants to assess telehealth ICAP efficacy. Results & Conclusions. The average change score on the WAB-R AQ for the telehealth cohort (5.42) was similar to the in-person cohorts (5.28), suggesting that telehealth delivery for ICAPs may be as efficacious as in-person delivery. Significance. COVID-19 has changed the landscape of stroke rehabilitation for people living with aphasia – particularly for those living in rural regions like the Mountain West. Telehealth models of service delivery have the potential to increase access to post-stroke services for rural residents beyond the pandemic era. Preliminary evidence suggests that telehealth delivery of an ICAP has the potential to result in similar language outcomes as in-person ICAP delivery

Oxytocin Receptor Genotype Modulates Ventral Striatal Activity to Social Cues and Response to Stressful Life Events

Background Common variants in the oxytocin receptor gene (OXTR) have been shown to influence social and affective behavior and to moderate the effect of adverse experiences on risk for social-affective problems. However, the intermediate neurobiological mechanisms are not fully understood. Although human functional neuroimaging studies have reported that oxytocin effects on social behavior and emotional states are mediated by amygdala function, animal models indicate that oxytocin receptors in the ventral striatum (VS) modulate sensitivity to social reinforcers. This study aimed to comprehensively investigate OXTR-dependent brain mechanisms associated with social-affective problems. Methods In a sample of 1445 adolescents we tested the effect of 23-tagging single nucleotide polymorphisms across the OXTR region and stressful life events (SLEs) on functional magnetic resonance imaging blood oxygen level-dependent activity in the VS and amygdala to animated angry faces. Single nucleotide polymorphisms for which gene-wide significant effects on brain function were found were then carried forward to examine associations with social-affective problems. Results A gene-wide significant effect of rs237915 showed that adolescents with minor CC-genotype had significantly lower VS activity than CT/TT-carriers. Significant or nominally significant gene × environment effects on emotional problems (in girls) and peer problems (in boys) revealed a strong increase in clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-homozygotes. However, in low-SLE environments, CC-homozygotes had more emotional problems (girls) and peer problems (boys). Moreover, among CC-homozygotes, reduced VS activity was related to more peer problems. Conclusions These findings suggest that a common OXTR-variant affects brain responsiveness to negative social cues and that in "risk- carriers" reduced sensitivity is simultaneously associated with more social-affective problems in "favorable environments" and greater resilience against stressful experiences. © 2014 Society of Biological Psychiatry

Membrane Association of the PTEN Tumor Suppressor: Molecular Details of the Protein-Membrane Complex from SPR Binding Studies and Neutron Reflection

The structure and function of the PTEN phosphatase is investigated by studying its membrane affinity and localization on in-plane fluid, thermally disordered synthetic membrane models. The membrane association of the protein depends strongly on membrane composition, where phosphatidylserine (PS) and phosphatidylinositol diphosphate (PI(4,5)P2) act pronouncedly synergistic in pulling the enzyme to the membrane surface. The equilibrium dissociation constants for the binding of wild type (wt) PTEN to PS and PI(4,5)P2 were determined to be Kd∼12 µM and 0.4 µM, respectively, and Kd∼50 nM if both lipids are present. Membrane affinities depend critically on membrane fluidity, which suggests multiple binding sites on the protein for PI(4,5)P2. The PTEN mutations C124S and H93R show binding affinities that deviate strongly from those measured for the wt protein. Both mutants bind PS more strongly than wt PTEN. While C124S PTEN has at least the same affinity to PI(4,5)P2 and an increased apparent affinity to PI(3,4,5)P3, due to its lack of catalytic activity, H93R PTEN shows a decreased affinity to PI(4,5)P2 and no synergy in its binding with PS and PI(4,5)P2. Neutron reflection measurements show that the PTEN phosphatase “scoots" along the membrane surface (penetration <5 Å) but binds the membrane tightly with its two major domains, the C2 and phosphatase domains, as suggested by the crystal structure. The regulatory C-terminal tail is most likely displaced from the membrane and organized on the far side of the protein, ∼60 Å away from the bilayer surface, in a rather compact structure. The combination of binding studies and neutron reflection allows us to distinguish between PTEN mutant proteins and ultimately may identify the structural features required for membrane binding and activation of PTEN

Refusing welfare gains: A study of FDA import refusal practices in the United States

Recent research shows that Sanitary and Phytosanitary (SPS) measures can act as barriers to trade, particularly impacting developing countries. This work analyzes the role of FDA import refusals as barriers to trade, particularly identifying their impacts on the US. This paper builds a theoretical framework based on the Specific Factors model in order to show that increased enforcement of SPS measures increases prices and decreases welfare. The analysis finds that on average increases in the probability of refusal have a negative effect at the extensive margin and zero effect at the intensive margin. For some industries, increases in the probability of refusal lead to decreased import values, which indicates welfare losses from this barrier to trade

The Order-Disorder Continuum: Linking Predictions of Protein Structure and Disorder through Molecular Simulation

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions within proteins (IDRs) serve an increasingly expansive list of biological functions, including regulation of transcription and translation, protein phosphorylation, cellular signal transduction, as well as mechanical roles. The strong link between protein function and disorder motivates a deeper fundamental characterization of IDPs and IDRs for discovering new functions and relevant mechanisms. We review recent advances in experimental techniques that have improved identification of disordered regions in proteins. Yet, experimentally curated disorder information still does not currently scale to the level of experimentally determined structural information in folded protein databases, and disorder predictors rely on several different binary definitions of disorder. To link secondary structure prediction algorithms developed for folded proteins and protein disorder predictors, we conduct molecular dynamics simulations on representative proteins from the Protein Data Bank, comparing secondary structure and disorder predictions with simulation results. We find that structure predictor performance from neural networks can be leveraged for the identification of highly dynamic regions within molecules, linked to disorder. Low accuracy structure predictions suggest a lack of static structure for regions that disorder predictors fail to identify. While disorder databases continue to expand, secondary structure predictors and molecular simulations can improve disorder predictor performance, which aids discovery of novel functions of IDPs and IDRs. These observations provide a platform for the development of new, integrated structural databases and fusion of prediction tools toward protein disorder characterization in health and disease.ONR (grant # N00014–16–1–651 2333)NIH U01 EB01497

Preoperative counts of CD4 T-lymphocytes and early postoperative infective complications in HIV-positive patients

To assess the relationship between postoperative infective complications and the CD4 count

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

BACKGROUND: The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(−/−) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(−/−) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (p(empirical) < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(−/−) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(−/−) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes